The overall goal of this proposed project is to clarify the roles of prostaglandins and leukotrienes in inflammatory rheumatic diseases. A major approach is to modify inflammation and immune responses by changes in the polyunsaturated fatty acid composition of dietary lipids. The n-3 fatty acids from dietary marine lipids are incorporated into tissues resulting in changes in the synthesis of eicosanoid mediators, prostaglandins and leukotrienes. This work has shown that dietary marine lipids modify certain inflammatory and immune reactions in experimental animals. Dietary marine lipids prolong lifespan and inhibit the development of autoimmune glomerulonephritis in murine lupus strains, and work planned will investigate the effects of these dietary lipids on other organ systems in murine lupus. Studies of purified components of marine lipids, such as eicosapentaenoic acid, will attempt to determine the protective factor(s) for murine lupus and other inflammatory processes. On the basis of these studies we are planning clinical trial of the therapeutic effects of dietary marine lipids on human systemic lupus erythematosus. Other experimental studies will examine the effects of these lipids on animal models for rheumatoid arthritis, acute hypersensitivity reactions, antibody formation, osteoclastic bone resorption and the reactivity of pulmonary tissue to leukotrienes. Effects of eicosanoids on immunoregulation will be studied in well-defined in vitro systems using T cell hybridoma lines. Finally, we will define further a new kinetic mechanism for the regulation of prostaglandin biosynthesis. We will also continue our experiments which indicate that inhibition of PG synthesis by glucocorticoids does not require phospholipase inhibition.